Glutamate carboxypeptidase II (GCPII) is an important target for the treatment of a number of neurological conditions, as well as for diagnostic imaging and treatment of prostate cancer. The enzyme is a membrane- bound metallopeptidase with well-characterized enzymatic activities. Development of GCPII inhibitors is a promising approach for the identification of neuroprotective agents that could be useful to treat a number of human ailments, including traumatic brain injury, stroke, amytrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and other diseases. While several inhibitor designs have obtained potent in vitro activity, developing such compounds into useful drugs is complicated by pharmacokinetic issues. Particularly, GCPII inhibitors are often highly charged molecules that are not orally bioavailable and/or do not pass through the blood brain barrier, limiting their use to treat neurological conditions. These studies will attempt to establish new classes of GCPII inhibitors which are expected to be potent and have improved pharmacokinetic properties. Another goal of these studies will be to examine the effect of isosteric variation on inhibitor potency. Specific Aims: (1) Development of novel N-hydroxyglutamyl inhibitors of glutamate carboxypeptidase II (2) Develop novel glutamyl sulfonamides as inhibitors of glutamate carboxypeptidase II using a structure-based approach (3) Modify glutamate carboxypeptidase II inhibitors to improve pharmacokinetics. Project Narrative: Relevance to public health GCPII inhibitors are a promising treatment for a number of significant neurological conditions, and through their interaction with this enzyme, may serve as neuroprotective drugs. Furthermore, as GCPII is over expressed in prostate cancer, the use of small molecule inhibitors to target for this protein for bioimaging and cancer therapy is a very important goal.